- Remarkable Enhancement of Enantioselectivity in the Asymmetric Conjugate Addition of Dimethylzinc to (Z)-Nitroalkenes with a Catalytic [(MeCN)4Cu]PF6-Hoveyda Ligand Complex
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An enantioselective copper-catalyzed asymmetric conjugate addition of Me2Zn to (Z)-nitroalkenes led to the formation of all-carbon quaternary stereogenic centers with high stereoselectivity. The key features of the new method are the unprecedented use of [(MeCN)4Cu]PF6 in conjunction with the Hoveyda ligand L1 and the use of (Z)-nitroalkene substrates so that undesired nitroalkene isomerization is minimized and enantioselectivity is enhanced dramatically. We also describe a novel, practical, and highly (Z)-selective nitroalkene synthesis.
- Zeng, Xingzhong,Gao, Joe J.,Song, Jinhua J.,Ma, Shengli,Desrosiers, Jean-Nicolas,Mulder, Jason A.,Rodriguez, Sonia,Herbage, Melissa A.,Haddad, Nizar,Qu, Bo,Fandrick, Keith R.,Grinberg, Nelu,Lee, Heewon,Wei, Xudong,Yee, Nathan K.,Senanayake, Chris H.
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- Combined Photoredox and Carbene Catalysis for the Synthesis of γ-Aryloxy Ketones
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N-heterocyclic carbenes (NHCs) have emerged as catalysts for the construction of C?C bonds in the synthesis of substituted ketones under single-electron processes. Despite these recent reports, there still remains a need to increase the utility and practicality of these reactions by exploring new radical coupling partners. Herein, we report the synthesis of γ-aryloxyketones via combined NHC/photoredox catalysis. In this reaction, an α-aryloxymethyl radical is generated via oxidation of an aryloxymethyl potassium trifluoroborate salt, which is then added into styrene derivatives to provide a stabilized benzylic radical. Subsequent radical-radical coupling reaction with an azolium radical affords the γ-aryloxy ketone products. (Figure presented.).
- Wang, Pengzhi,Fitzpatrick, Keegan P.,Scheidt, Karl A.
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supporting information
p. 518 - 524
(2021/12/16)
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- Practical Chemoselective Acylation: Organocatalytic Chemodivergent Esterification and Amidation of Amino Alcohols with N-Carbonylimidazoles
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Chemoselective transformations are a cornerstone of efficient organic synthesis; however, achieving this goal for even simple transformations, such as acylation reactions, is often a challenge. We report that N-carbonylimidazoles enable catalytic chemodivergent aniline or alcohol acylation in the presence of pyridinium ions or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), respectively. Both acylation reactions display high and broad chemoselectivity for the target group. Unprecedented levels of chemoselectivity were observed in the DBU-catalyzed esterification: A single esterification product was obtained from a molecule containing primary aniline, alcohol, phenol, secondary amide, and N?H indole groups. These acylation reactions are highly practical as they involve only readily available, inexpensive, and relatively safe reagents; can be performed on a multigram scale; and can be used on carboxylic acids directly by in situ formation of the acylimidazole electrophile.
- Brown, Hailee,Heller, Stephen T.,Light, Christina,Medlin, Abigail,Nelson, Hope,Richard, William
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supporting information
p. 22818 - 22825
(2021/09/13)
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- Silver-Catalyzed Acyl Nitrene Transfer Reactions Involving Dioxazolones: Direct Assembly of N-Acylureas
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Dioxazolones and isocyanides are useful synthetic building blocks, and have attracted significant attention from researchers. However, the silver-catalyzed nitrene transfer reaction of dioxazolones has not been investigated to date. Herein, a silver-catalyzed acyl nitrene transfer reaction involving dioxazolones, isocyanides, and water was realized in the presence of Ag2O to afford a series of N-acylureas in moderate to good yields.
- Yang, Zheng-Lin,Xu, Xin-Liang,Chen, Xue-Rong,Mao, Zhi-Feng,Zhou, Yi-Feng
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supporting information
p. 648 - 652
(2020/12/21)
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- Synthesis of Dithiolethiones and Identification of Potential Neuroprotective Agents via Activation of Nrf2-Driven Antioxidant Enzymes
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Oxidative stress is implicated in the pathogenesis of a wide variety of neurodegenerative disorders, and accordingly, dietary supplement of exogenous antioxidants or/and upregulation of the endogenous antioxidant defense system are promising for therapeutic intervention or chemoprevention of neurodegenerative diseases. Nrf2, a master regulator of the cellular antioxidant machinery, cardinally participates in the transcription of cytoprotective genes against oxidative/electrophilic stresses. Herein, we report the synthesis of 59 structurally diverse dithiolethiones and evaluation of their neuroprotection against 6-hydroxydopamine-or H2O2-induced oxidative damages in PC12 cells, a neuron-like rat pheochromocytoma cell line. Initial screening identified compounds 10 and 11 having low cytotoxicity but conferring remarkable protection on PC12 cells from oxidative-mediated damages. Further studies demonstrated that both compounds upregulated a battery of antioxidant genes as well as corresponding genes' products. Significantly, silence of Nrf2 expression abolishes cytoprotection of 10 and 11, indicating targeting Nrf2 activation is pivotal for their cellular functions. Taken together, the two lead compounds discovered here with potent neuroprotective functions against oxidative stress via Nrf2 activation merit further development as therapeutic or chemopreventive candidates for neurodegenerative disorders.
- Bai, Feifei,Fang, Jianguo,Song, Zi-Long,Zhang, Baoxin
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p. 2214 - 2231
(2020/03/06)
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- Combined Photoredox and Carbene Catalysis for the Synthesis of Ketones from Carboxylic Acids
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As a key element in the construction of complex organic scaffolds, the formation of C?C bonds remains a challenge in the field of synthetic organic chemistry. Recent advancements in single-electron chemistry have enabled new methods for the formation of various C?C bonds. Disclosed herein is the development of a novel single-electron reduction of acyl azoliums for the formation of ketones from carboxylic acids. Facile construction of the acyl azolium in situ followed by a radical–radical coupling was made possible merging N-heterocyclic carbene (NHC) and photoredox catalysis. The utility of this protocol in synthesis was showcased in the late-stage functionalization of a variety of pharmaceutical compounds. Preliminary investigations using chiral NHCs demonstrate that enantioselectivity can be achieved, showcasing the advantages of this protocol over alternative methodologies.
- Betori, Rick C.,Davies, Anna V.,Fitzpatrick, Keegan P.,Scheidt, Karl A.
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supporting information
p. 9143 - 9148
(2020/03/30)
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- Ketoreductase catalyzed stereoselective bioreduction of α-nitro ketones
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We report here the stereoselective bioreduction of α-nitro ketones catalyzed by ketoreductases (KREDs) with publicly known sequences. YGL039w and RasADH/SyADH were able to reduce 23 class I substrates (1-aryl-2-nitro-1-ethanone (1)) and ten class II substrates (1-aryloxy-3-nitro-2-propanone (4)) to furnish both enantiomers of the corresponding β-nitro alcohols, with good-to-excellent conversions (up to >99%) and enantioselectivities (up to >99% ee) being achieved in most cases. To the best of our knowledge, KRED-mediated reduction of class II α-nitro ketones (1-aryloxy-3-nitro-2-propanone (4)) is unprecedented. Select β-nitro alcohols, including the synthetic intermediates of bioactive molecules (R)-tembamide, (S)-tembamide, (S)-moprolol, (S)-toliprolol and (S)-propanolol, were stereoselectively synthesized in preparative scale with 42% to 90% isolated yields, showcasing the practical potential of our developed system in organic synthesis. Finally, the advantage of using KREDs with known sequence was demonstrated by whole-cell catalysis, in which β-nitro alcohol (R)-2k, the key synthetic intermediate of hypoglycemic natural product (R)-tembamide, was produced in a space-time yield of 178 g L?1 d?1 as well as 95% ee by employing the whole cells of a recombinant E. coli strain coexpressing RasADH and glucose dehydrogenase as the biocatalyst.
- Wang, Zexu,Wu, Xiaofan,Li, Zhining,Huang, Zedu,Chen, Fener
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supporting information
p. 3575 - 3580
(2019/04/14)
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- Efficient CDI/CH3SO3H-catalyzed, microwave-assisted synthesis of 2-substituted benzothiazoles
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CDI combined with CH3SO3H was found to be highly effective for the cyclization of 2-aminothiophenol derivatives with carboxylic acids under MW condition. Fourteen benzothiazole derivatives were synthesized in good yield and their structures were characterized by1H-NMR,13C-NMR, IR and mass spectrometry. This simple, rapid synthetic method is believed to provide a useful process for the synthesis of 2-substituted benzothiazole compounds.
- Li, Yao-Wei,Zhang, Pei-Ming,Li, Rui,Bai, Yan,Yu, Yu,Gan, Zong-Jie
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supporting information
p. 34 - 39
(2019/05/04)
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- New bioactive triaryl triglyceride esters: Synthesis, characterization and biological activities
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Four new bioactive aryl triester derivatives of glycerol and benzoic acids were synthesized. The synthetic compounds were studied for their antimicrobial and urease inhibition activities. Esterification was carried out by using carbonyldiimidazole to enhance the acyl elimination addition reaction with benzoic acid derivatives. The structure of triglycerides were studied by EI-MS,1H,13C-NMR, FT-IR and elemental analysis. All synthetic compounds showed urease inhibition activity with highest value of IC50 value 22.4 ± 0.45 μM which is nearest to standard thiourea IC50 value (21.6 ± 0.12 μM). Except compound (3d), all other compounds exhibited antimicrobial activity against Streptococcus pneumoniae, Staphylococcus epidermidis, Bacillus pumilus, Escherichia coli, Pseudomonas aeruginosa and Candida albican.
- Arshad, Tanzila,Sheikh, Hamdullah Khadim,Kazmi, Mehdi Hassan,Farheen, Sadia,Sohail, Tehmina,Lateef, Mehreen
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p. 302 - 308
(2018/11/01)
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- Preliminary SAR and biological evaluation of antitubercular triazolothiadiazine derivatives against drug-susceptible and drug-resistant Mtb strains
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Following up the SAR study of triazolothiadiazoles for their antitubercular activities targeting Mt SD in our previous study, on the principle of scaffold hopping, the C3 and C6 positions of triazolothiadiazine were examined systematically to define a preliminary structure–activity relationship (SAR) with respect to biological activity. This study herein highlights the potential of two highly potent advanced leads 6c-3, 6g-3 and several other compounds with comparable potencies as promising new candidates for the treatment of TB (6c-3, MIC-H37Rv?=?0.25?μg/mL; MIC-MDRTB?=?2.0?μg/mL; MIC-RDRTB?=?0.25?μg/mL; Mt SD-IC50?=?86.39?μg/mL; and 6g-3, MIC-H37Rv?=?1.0?μg/mL; MIC-MDRTB?=?4.0?μg/mL; MIC-RDRTB?=?2.0?μg/mL; Mt SD-IC50?=?73.57?μg/mL). Compounds 6c-3 and 6g-3 possessed a para-nitro phenyl at the 6 position showed low Vero and HepG2 cells toxicity, turning out to be two excellent lead candidates for preclinical trials. In addition, in vitro Mt SD inhibitory assay indicates that Mt SD is at least one of the targets for their antitubercular activity. Thus, they may turn out to be promising multidrug-resistance-reversing agents.
- Li, Ziqiang,Bai, Xiaoguang,Deng, Qi,Zhang, Guoning,Zhou, Lei,Liu, Yishuang,Wang, Juxian,Wang, Yucheng
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p. 213 - 220
(2016/12/18)
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- Chemoselective acylation of 2-amino-8-quinolinol in the generation of C2-amides or C8-esters
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Two different ways to carry out the chemoselective acylation of 2-amino-8-quinolinol with unique features to generate C2-amides or C8-esters were developed. The coupling reaction with a variety of carboxylic acids using EDCI and DMAP provided C8-ester derivatives, whereas N-heteroaromatic acids were not introduced on the C8-hydroxy group, but rather on the C2-amino group under the same conditions. To obtain C2-amides selectively, the anionic nucleophile from 2-amino-8-quinolinol was treated with less reactive acyl imidazolides or esters.
- Park, Yongseok,Fei, Xiang,Yuan, Yue,Lee, Sanha,Hur, Joonseong,Park, Sung Jean,Jung, Jae-Kyung,Seo, Seung-Yong
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p. 41955 - 41961
(2017/09/12)
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- An Environmentally Sustainable Mechanochemical Route to Hydroxamic Acid Derivatives
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An operationally simple, and cost efficient conversion of carboxylic acids into hydroxamic acid derivatives via a high-energy mechanochemical activation is presented. This ball milling methodology was applied to a wide variety of carboxylic acids dramatically improving purification issues associated with this class of molecules, which still remain one of the main bottlenecks of classical methodologies. (Figure presented.).
- Mocci, Rita,De Luca, Lidia,Delogu, Francesco,Porcheddu, Andrea
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supporting information
p. 3135 - 3144
(2016/10/09)
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- An efficient synthesis of 1,3,7-triazaspiro[4.4]nonane-2,4-dione derivatives and antimicrobial activity thereof
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Efficient methods for the synthesis of 1,3,7-triazaspiro[4.4]nonane-2,4-dione derivatives possessing an unsaturated pyrrolidine cycle have been developed affording intermediates and target compounds in high yields not requiring additional purification. Antimicrobial activity of the synthesized compounds was studied.
- Krolenko, Konstantin Yu.,Silin, Olexiy V.,Vlasov, Sergiy V.,Zhuravel, Irina O.,Kovalenko, Sergiy M.
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p. 472 - 477
(2015/10/19)
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- SAR studies on 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles as inhibitors of Mtb shikimate dehydrogenase for the development of novel antitubercular agents
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Shikimate dehydrogenase, an essential protein for the biosynthesis of the chorismate end product, is a highly promising therapeutic target, especially for the discovery and development of new-generation anti-TB agents. Following up the identification of one lead 3,6-disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (1), targeting Mt SD in our previous study, an extensive SAR study for optimization of the lead compound was performed through systematic modification of the 3 and 6 positions. This study has successfully led to the discovery of two highly potent advanced leads 6d-4, 6c-4 and several other compounds with comparable potencies (6d-4, MIC-H37Rv = 0.5 μg mL-1; MIC-MDRTB = 4.0 μg mL-1; MIC-RDRTB = 0.5 μg mL-1; Mt SD-IC50 = 14.20 μg mL-1; and 6c-4, MIC-H37Rv = 0.5 μg mL-1; MIC-MDRTB = 4.0 μg mL-1; MIC-RDRTB = 1.0 μg mL-1; Mt SD-IC50 = 6.82 μg mL-1). These advanced lead compounds possess a para-halogen phenyl at the 3 position. In vitro Mt SD inhibitory assay indicates that Mt SD is the target for their antitubercular activity. Moreover, the BacT/ALERT 3D liquid culture technology and in vitro Mt SD inhibitory assay were initially applied.
- Li, Ziqiang,Liu, Yishuang,Bai, Xiaoguang,Deng, Qi,Wang, Juxian,Zhang, Guoning,Xiao, Chunling,Mei, Yaning,Wang, Yucheng
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p. 97089 - 97101
(2015/12/01)
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- N-methylimidazole-catalyzed synthesis of carbamates from hydroxamic acids via the lossen rearrangement
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An efficient, one-pot, N-methylimidazole (NMI) accelerated synthesis of aromatic and aliphatic carbamates via the Lossen rearrangement is reported. NMI is a catalyst for the conversion of isocyanate intermediates to the carbamates. Moreover, the utility of arylsulfonyl chloride in combination with NMI minimizes the formation of often-observed hydroxamate-isocyanate dimers during the sequence. Under the present conditions, lowering of temperatures is also possible, enabling a mild protocol.
- Yoganathan, Sabesan,Miller, Scott J.
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supporting information
p. 602 - 605
(2013/04/11)
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- Novel 5-substituted 1H-tetrazoles as cyclooxygenase-2 (COX-2) inhibitors
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A series of novel 5-substituted 1H-tetrazoles as cyclooxygenase-2 (COX-2) inhibitors was prepared via treatment of various diaryl amides with tetrachlorosilane/sodium azide. All compounds were tested in cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Tetrazoles contained a methylsulfonyl or sulfonamide group as COX-2 pharmacophore displayed only low inhibitory potency towards COX-2. Most potent compounds showed IC50 values of 6 and 7 μM for COX-2. All compounds showed IC50 values greater 100 μM for COX-1 inhibition.
- Al-Hourani, Baker Jawabrah,Sharma, Sai Kiran,Suresh, Mavanur,Wuest, Frank
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supporting information; experimental part
p. 2235 - 2238
(2012/04/18)
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- Asymmetric Rh(II)-catalyzed cyclopropanation of alkenes with diacceptor diazo compounds: P -methoxyphenyl ketone as a general stereoselectivity controlling group
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Different diacceptor diazo compounds bearing an α-PMP-ketone group were found to be effective carbene precursors for the highly stereoselective Rh2(S-TCPTTL)4-catalyzed cyclopropanation of alkenes (EWG = NO2, CN, CO2Me). The resulting products were readily transformed into a variety of biologically relevant enantiopure molecules, such as cyclopropane α- and β-amino acid derivatives. Different mechanistic studies carried out led to a rationale for the high diastereo- and enantioselectivity obtained, where the PMP-ketone moiety was found to play a critical role in the stereoinduction process. Additionally, the use of catalytic amounts of achiral Lewis bases to influence the enantioinduction of the reactions developed is documented.
- Lindsay, Vincent N. G.,Nicolas, Cyril,Charette, Andre B.
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supporting information; experimental part
p. 8972 - 8981
(2011/08/04)
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- Discovery of Benzamide Analogues as a Novel Class of 5-HT3 Receptor Agonists
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A 5-HT3 receptor agonist based on a benzamide scaffold was identified in a screening of a small commercial compound library, and an elaborate SAR study originating from this hit was performed. The design, synthesis, and functional characterisation of benzamide analogues at the 5-HT3A receptor yielded substantial information concerning the analogues as 5-HT3 receptor agonists. However, the potencies of the derived analogues were not significantly improved over that of the initial hit. The benzamide scaffold constitutes a novel type of 5-HT3 receptor agonist, as it does not possess a positively charged functionality, which is essential for the binding of all orthosteric ligands to the receptor. Preliminary investigations suggest that the compounds may exert their effects on 5-HT3 receptors by binding to an allosteric site in the receptor complex.
- Jorgensen, Charlotte G.,Frolund, Bente,Kehler, Jan,Jensen, Anders A.
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scheme or table
p. 725 - 736
(2012/01/06)
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- Activation of imidazolides using methyl trifluoromethanesulfonate: A convenient method for the preparation of hindered esters and amides
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Treatment of imidazolides with methyl trifluoromethanesulfonate followed by reaction with alcohols or amines provides a convenient one-pot procedure for the preparation of esters and amides. The method is applicable to imidazolides of low reactivity as well as to hindered nucleophiles.
- Ulibarri, Gerardo,Choret, Nadege,Bigg, Dennis C. H.
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p. 1286 - 1288
(2007/10/03)
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- REACTIONS OF SOME 1-(4,5-DIHYDROIMIDAZOL-2-YL)AZOLES WITH AROYL AND ETHOXYCARBONYL ISOTHIOCYANATES
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Three components cyclocondensations of the imidazole derivative (1c) with aroyl isothiocyanates afforded 6,7,8,8a-tetrahydro-3-aroylimidazotriazine-2,4(3H,8H)-dithiones (5a-e) while similar reaction with ethoxycarbonyl isothiocyanate led to the formation of ethyl 5-thioxo-2,3,8,9-tetrahydro-5H-diimidazotriazine-6-carboxylate (10).
- Saczewski, Franciszek
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p. 689 - 692
(2007/10/02)
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